The present invention relates to an advantageous process for the preparation of fluoroquinolonecarboxylic acids by acidic hydrolysis of the corresponding fluoroquinolonecarboxylic acid esters.
Fluoroquinolonecarboxylic acids are-important intermediates for the preparation of known pharmaceutically active compounds from the class consisting of the quinolones.
It is known (see EP-A 169,993) that cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid esters can be hydrolyzed under acidic or basic conditions to give the corresponding quinolonecarboxylic acids (loc. cit. page 10, lines 4 to 7). The hydrolysis of-94 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydroxy-4-oxo-3-quinolinecarboxylate acid with addition of water, glacial acetic acid, and 70 ml (128.8 g) of concentrated sulfuric acid (which corresponds to about 420 g of sulfuric acid per mole of the fluoroquinolonecarboxylic acid ester) is now described in more concrete terms, the reaction mixture being heated under reflux for 1.5 hours, then the suspension present being poured onto ice and then the precipitate that is present being filtered off with suction, washed, and dried (loc. cit. page 28, last paragraph). The yield here is 96% of theory.
A disadvantage of this process is the large amount of sulfuric acid that is needed, the large amounts of waste water and the disposal problems thus resulting, which result from the use of large amounts of sulfuric acid (which is then obtained as dilute acid) and ice, and the necessity to wash the isolated product a number of times in order to remove adhering sulfuric acid residues.
There has now been found a process for the preparation of fluoroquinolonecarboxylic acids by hydrolysis of the corresponding C1-C4-alkyl esters comprising
(a) mixing water, acetic acid, and sulfuric acid with a C1-C4-alkyl fluoroquinolonecarboxylate, wherein less than 30 g of sulfuric acid per 1 mol of C1-C4-alkyl fluoroquinolonecarboxylate are employed,
(b) heating the resultant reaction mixture at reflux for 0.5 to 8 hours,
(c) distilling off a mixture of acetic acid, C1-C4-alkyl acetate, C1-C4-alkyl alcohol, and optionally water, and
(d) isolating the resultant fluoroquinolonecarboxylic acid.
Suitable C1-C4-alkyl fluoroquinolonecarboxylates to be employed are, for example, those of the formula (I) 
in which
R1 represents C1-C4-alkyl,
R2 represents hydrogen, C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro, or cyano,
R3 and R4 each represent halogen,
R5 represents hydrogen, C1-C4-alkyl, halogen, or nitro, and
Y represents C1-C6-alkyl, cyclopropyl, or phenyl, each of which is optionally substituted by halogen, or R2 and Y together represent a xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 orxe2x80x94-CH(CH3)xe2x80x94CH2xe2x80x94Oxe2x80x94 bridge bonded to the quinolone ring nitrogen atom by a carbon atom,
with the proviso that at least one of the radicals R2 to R5 represents fluorine.
Starting from the C1-C4-alkyl fluoroquinolonecarboxylates of the formula (I), for example, it is possible to obtain the corresponding fluoroquinolonecarboxylic acids of the formula (II) 
in which the radicals R2 to R5 and Y have the meaning indicated for formula (I).
Preferably, in the formulas (I) and (II),
R2 represents hydrogen, methyl, methoxy, fluorine, chlorine, nitro, or cyano,
R3 represents fluorine or chlorine,
R4 represents fluorine,
R5 represents hydrogen, methyl, fluorine, chlorine, or nitro, and
Y represents methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluorophenyl, or 2,4-difluorophenyl.
Preferably, in formula (I) R1 represents methyl or ethyl.
In the process according to the invention, acetic acid and sulfuric acid can be employed in water-containing or anhydrous form. The quantitative data described relate to 100% strength acetic acid and 100% strength sulfuric acid. If water-containing acetic acid and/or water-containing sulfuric acid is employed, less water must be employed according to their water content. Acetic acid is preferably employed in the form of glacial acetic acid, and sulfuric acid is preferably employed in the form of 96 to 100% strength sulfuric acid.
Relative to 1 mol of C1-C4-alkyl fluoroquinolonecarboxylate, it is possible to employ in the process according to the invention, for example, 20 to 250 ml of water, 200 to 2000 ml of acetic acid, and 2 to 25 g of sulfuric acid. Preferably, the amounts are 100 to 200 ml of water, 300 to 1000 ml of acetic acid, and 3 to 15 g of sulfuric acid.
The addition of water, acetic acid, and sulfuric acid is preferably carried out such that the C1-C4-alkyl fluoroquinolonecarboxylate, the water, and the acetic acid are introduced before the sulfuric acid is added.
The reaction mixture is preferably heated to reflux for 1 to 5 hours.
After completion of the heating to reflux, acetic acid, C1-C4-alkyl acetate, C1-C4-alkyl alcohol, and water are distilled off from the reaction mixture. The distillation can be conducted, for example, until a bottom temperature in the range from 107 to 113xc2x0 C. results. The distillation is preferably conducted until a bottom temperature in the range from 108 to 110xc2x0 C. results. These temperatures relate to normal pressure. If the reaction is carried out at other pressures, these temperatures are to be set correspondingly lower or higher.
The 3 to 4 components distilling off in the distillation distil, inter alia, in the form of azeotropes for which the composition can change during the distillation.
The heating of the reaction mixture to reflux and the subsequent distillation can be carried out at reduced pressure, atmospheric pressure, or elevated pressure. For example, pressures in the range from 0.5 to 3 bar are possible. Preferably, both process steps are carried out at atmospheric pressure.
The fluoroquinolonecarboxylic acid prepared from the mixture present after the distillation can be isolated, for example, by diluting this mixture with water and filtering off the precipitate then present with suction, washing the precipitate with water, and drying it. It is advantageous to wash the isolated product a number of times in order to obtain it sufficiently free and largely without adhering sulfuric acid.
Preferably, the isolation of the fluoroquinolonecarboxylic acid prepared is carried out by setting a pH in the range from 2 to 5 (preferably 3 to 4) in the mixture that is present after the distillation by addition of a base. This can be achieved, for example, by adding an appropriate amount of sodium hydroxide solution or sodium acetate. Preferably, a 1 to 20% strength by weight aqueous sodium acetate solution is used. The pH optimal for the isolation of a specific fluoroquinolonecarboxylic acid can be determined by a simple titration. The pH resulting from the titration is therefore chosen on the one hand to be as high as possible but on the other hand not so high as to lead to the precipitation of the salts of the respective fluoroquinolonecarboxylic acid. After setting the pH, the mixture can be cooled, for example, to 0 to 35xc2x0 C., and the precipitate then present can be filtered off, washed with water, and dried. The drying is preferably carried out at elevated temperature and reduced pressure. As a rule, an adequately pure product can be obtained even with a single washing.
Using the process according to the invention, fluoroquinolonecarboxylic acids are in general obtained in yields of 98% of theory and higher.
In the manner according to the invention, it is particularly possible to obtain the following fluoroquinolonecarboxylic acids in an advantageous manner: 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 1-cyclopropyl-6,7-difluoro-8-cyano-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-(2-fluoro)cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, and 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
The process according to the invention has the advantage that, compared with the prior art, very much less sulfuric acid (only about 1 to 10% of the amount previously used) is employed and therefore the amount of dilute acid formed is significantly lower. If the advantageous, pH-controlled method for the isolation of the fluoroquinolonecarboxylic acids that is prepared is also used, washing operations can be avoided and further reductions in the amount of waste water realized. Finally, the yield of desired product is higher than previously obtained.
The advantages resulting according to the invention are very surprising, since if only the amount of sulfuric acid is reduced compared with the prior art but the distillation is not carried out or if the amount of sulfuric acid is reduced and the mixture is only briefly heated to reflux, then the hydrolysis no longer proceeds almost quantitatively but instead proceeds only incompletely, which leads to reductions in yield and product impurities (see comparison examples).
The following examples further illustrate details for the process of this invention. The invention, which is set forth in the foregoing disclosure, is not to be limited either in spirit or scope by these examples. Those skilled in the art will readily understand that known variations of the conditions of the following procedures can be used. Unless otherwise noted, all temperatures are degrees Celsius and all percentages are percentages by weight.